Perturbations affecting normal development of the ovaries during embryogenesis and fetal growth can lead to reproductive disorders such as infertility, premature ovarian failure, or ovarian cancer. However, little is known about the factors and cellular events underlying normal fetal ovarian development. Recent observations indicate that the transcription factor GATA4 is a regulator of fetal ovarian development, however its exact function is not known. The long-term goal of our research is to obtain a better understanding of the cellular and molecular events controlling development and differentiation of the mammalian fetal ovaries. The central hypothesis that will be tested in this proposal is that GATA4 controls fetal ovarian somatic cell differentiation by regulating cell cycle progression. To test our hypothesis the following specific aims are proposed: (1) Determine how GATA4 regulates fetal ovarian somatic cell proliferation. (2) Determine if GATA4 interacts with the TGF[unreadable] signaling pathway during fetal ovarian somatic cell differentiation. The proposed aims will be accomplished by using a unique transgenic mouse model in which GATA4 is specifically deleted in fetal ovarian somatic cells, and by using molecular approaches to assess GATA4 interaction with the cell cycle program, and TGF[unreadable] mediated control of fetal ovarian somatic cell differentiation. This proposal is innovative because it provides insight into the cellular and molecular events regulating fetal ovarian development, and novel because it will identify a function for GATA4 in mammalian fetal ovarian somatic cells. Determining the role of GATA4 in fetal ovarian development will offer important insight into female reproductive disease such as ovarian cancer, as abnormal GATA4 expression has been observed in ovarian tumors. PUBLIC HEALTH RELEVANCE: Any perturbations in the process of fetal ovarian development and differentiation can lead to a range of severe adverse consequences in adulthood, including infertility and ovarian cancer. Ovarian cancer is the most lethal gynecological malignancy in women because it often is detected at a late stage when tumor growth has spread to other tissues. A gene abnormally expressed in ovarian tumors is Gata4. This research aims to identify the role of Gata4 during fetal ovarian development, which will provide important information about the mechanism controlling early fetal ovarian somatic cell proliferation, and is essential to obtain insight into female reproductive disorders and disease.